Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. The IL-17 family of cytokines includes IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F, and the prototype member of the family has been designated IL-17A (see, e.g., Moseley et al., Cytokine Growth Factor Rev., 14(2): 155-74 (2003)). All members of the IL-17 family have a similar protein structure, with four highly conserved cysteine residues critical to their three-dimensional shape, yet they have no sequence similarity to any other known cytokines. However, a viral homologue of IL-17A has been found in open reading frame 13 of Herpesvirus saimiri (see, e.g., Yao et al., Immunity, 3: 811 (1995)), which has 72% amino acid residue identity to human IL-17A.
Multiple functions have been reported for the IL-17 family members, which primarily involve regulation of the immune response. For example, IL-17 is involved in upregulating adhesion molecules and inducing the production of multiple inflammatory cytokines and chemokines from various cell types, including synoviocytes, chondrocytes, fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages. Also, IL-17 induces recruitment of neutrophils to an inflammatory site through induction of chemokine release, stimulates production of prostaglandins and metalloproteinases, and inhibits proteoglycan synthesis. IL-17 plays an important role in the maturation of hematopoietic progenitor cells, and IL-17 appears to have signaling roles in different organs and tissues including lung, articular cartilage, bone, brain, hematopoietic cells, kidney, skin, and intestine (see, e.g., Kolls and Linden, Immunity, 21: 467-476 (2004), and Fossiez, et al., Int. Rev. Immunol., 16: 541 (1998)). IL-17 also induces matrix metalloproteinases (MMP) production and downregulates tissue inhibitor of metalloproteinases (TIMPs) (see, e.g., Jovanovic et al., J. Rheumatol., 28: 712-718 (2001)), and blockage of IL-1 and IL-17 has a synergistic effect on inflammation and bone destruction in vivo (see, e.g., Chabaud et al., Arthritis Rheum., 44: 1293-1303 (2001)).
Inappropriate or increased production of IL-17 (i.e., IL-17A) has been associated with several diseases, such as airway inflammation, asthma, rheumatoid arthritis (RA), osteoarthritis, osteoporosis, bone erosion, intraperitoneal abscesses and adhesions, inflammatory bowel disorder (IBD), chronic obstructive pulmonary disorder (COPD), Addison's disease, agammaglobulinemia, allergic asthma, alopecia greata, Celiac spruce, Chagas disease, idiopathic pulmonary fibrosis, Crohn's disease, ulcerative colitis, allograft rejection (e.g., renal), psoriatic arthritis, uveitis, Behcet's disease, certain types of cancer, angiogenesis, atherosclerosis, multiple sclerosis (MS), systemic lupus erythematosus, septicemia, septic or endotoxic shock, response to allergen exposure, Helicobacter pylori-associated gastritis, bronchial asthma, ankylosing spondylitis, lupus nephritis, psoriasis, ischemia, systemic sclerosis, stroke, and other inflammatory disorders (see, e.g., Witowski et al., Cell Mol. Life. Sci., 61: 567-579 (2004); Antonysamy et al., J. Immunol., 162: 577-584 (1999), van Kooten et al., J. Am. Soc. Nephrol., 9: 1526-1534 (1998); Molet et al., J. Allergy Clin. Immunol., 108: 430-438 (2001); Teunissen et al., J. Invest. Dermatol., 111: 645-649 (1998); and Kurasawa et al., Arthritis Rheum., 43: 2455-2463 (2000)).
Based on the foregoing, IL-17 appears to be a target for the treatment of several inflammatory or autoimmune diseases. To this end, antibodies that bind IL-17 have been proposed for use in treating IL-17-mediated diseases and disorders (see, e.g., International Patent Application Publication Nos. WO 2006/013107 and WO 2007/117749; and U.S. Patent Application Publication Nos. 2008/0269467 A1 and 2009/0280131 A1). In addition, blocking of IL-17 bioactivity by an IL-17-specific antibody or soluble receptor binding to IL-17 reduces inflammation and bone erosion in various animal arthritis models (see, e.g., Lubberts et al., Arthritis & Rheumatism, 50: 650-659 (2004)). However, the therapeutic utility of currently available IL-17 antibodies is limited by their sub-optimum pharmacokinetics, stability and efficacy in vivo.
Therefore, there is a need for an IL-17-binding agent (e.g., an antibody) which binds IL-17 with a high affinity, exhibits increased stability and improved pharmacokinetics, and effectively neutralizes IL-17 activity in vivo. The invention provides such an IL-17 binding agent.